Glucose tolerance and peripheral insulin resistance are found in aging individuals. Any effective preventive or treatment measures require knowledge of the basic mechanisms underlying these changes and the relative importance of obesity and lack of exercise. Since evidence suggests that peripheral tissue, particularly skeletal muscle, is a major contributor to glucose intolerance in aging, the primary focus of this research is on the mechanism of muscle insulin resistance in aging and the influence of obesity and exercise on this parameter. For this purpose, the Zucker rat will be used as the experimental animal model. This unique model provides a means of separating out the two variables, obesity and aging, since the lean phenotype remains lean throughout its life span and the obese phenotype occurs on the same genetic background. The age-dependent development of in vivo glucose intolerance and insulin resistance of soleus and extensor digitorum longus muscles will be documented during the life span of lean and obese Zucker rats. The mechanism of insulin resistance will be investigated in isolated muscle preparations by measuring insulin receptor number and affinity through 125I-labeled insulin binding experiments. Glucose transport and phosphorylation, the number and regulation of glucose transport sites and glucose metabolism will also be determined in order to delineate the mechanism of insulin resistance in obesity and with age. Exercise training will be initiated in lean Zucker rats before the onset of glucose intolerance to see if exercise will prevent or delay the alterations normally seen in muscle insulin sensitivity with age. Insulin binding, glucose transport, glucose transport sites and glucose metabolism as mentioned above will be studied in exercise-trained rats and compared to sedentary, ad libitum-fed and sedentary, food-restricted rats. The data obtained will define the mechanism of muscle insulin resistance in aging and its relationship to in vivo glucose intolerance. The data also will determine the separate influences of obesity and lack of exercise on glucose intolerance and muscle insulin resistance in aging.